Alexander Semaan1, Barbara Uhl2, Vittorio Branchi3, Philipp Lingohr3, Friedrich Bootz4, Glen Kristiansen2, Jörg C Kalff3, Hanno Matthaei3, Dimitrios Pantelis3, Dimo Dietrich4. 1. Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany. Electronic address: papers.semaan@gmail.de. 2. Institute of Pathology, University Hospital Bonn, Bonn, Germany. 3. Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany. 4. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
Abstract
BACKGROUND: New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 (PITX2) promoter methylation in CRC patients. MATERIALS AND METHODS: Data of 2 independent cohorts were investigated. Tissue specimens of cohort A (n = 179) were analyzed for their methylation in the PITX2 promoter region using quantitative methylation-specific polymerase chain reaction and compared with publicly available data (PITX2 promoter methylation and PITX2 mRNA expression levels) from "The Cancer Genome Atlas Research Network" (cohort B, n = 443). Data were correlated with clinicopathological parameters and outcome. RESULTS: Tumor samples of both cohorts showed a decreased PITX2 promoter methylation level (both P < .001) compared with nonmalignant tissue. Additionally, PITX2 promoter hypomethylation was prognostic in univariate and multivariate analysis (hazard ratio [HR], 1.97 [95% confidence interval (CI), 1.12-3.47], P = .018 and HR, 1.89 [95% CI, 1.09-3.29], P = .023), and Kaplan-Meier analysis (median overall survival, 53.2 vs. 70.4 months, P = .004). Subanalysis of high-risk vs. low-risk stage II CRC patients also showed a PITX2 hypomethylation of the promoter region in the high-risk group (P = .006). CONCLUSION: Our results suggest a prognostic role of PITX2 promoter methylation in CRC as biomarker for risk stratification in stage II CRC patients although the results need to be independently validated.
BACKGROUND: New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 (PITX2) promoter methylation in CRC patients. MATERIALS AND METHODS: Data of 2 independent cohorts were investigated. Tissue specimens of cohort A (n = 179) were analyzed for their methylation in the PITX2 promoter region using quantitative methylation-specific polymerase chain reaction and compared with publicly available data (PITX2 promoter methylation and PITX2 mRNA expression levels) from "The Cancer Genome Atlas Research Network" (cohort B, n = 443). Data were correlated with clinicopathological parameters and outcome. RESULTS:Tumor samples of both cohorts showed a decreased PITX2 promoter methylation level (both P < .001) compared with nonmalignant tissue. Additionally, PITX2 promoter hypomethylation was prognostic in univariate and multivariate analysis (hazard ratio [HR], 1.97 [95% confidence interval (CI), 1.12-3.47], P = .018 and HR, 1.89 [95% CI, 1.09-3.29], P = .023), and Kaplan-Meier analysis (median overall survival, 53.2 vs. 70.4 months, P = .004). Subanalysis of high-risk vs. low-risk stage II CRC patients also showed a PITX2 hypomethylation of the promoter region in the high-risk group (P = .006). CONCLUSION: Our results suggest a prognostic role of PITX2 promoter methylation in CRC as biomarker for risk stratification in stage II CRC patients although the results need to be independently validated.